Metronomic chemotherapy (mCHT) in metastatic triple-negative breast cancer (TNBC) patients: results of the VICTOR-6 study.

PURPOSE: Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. METHODS: We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). RESULTS: Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9-7.2) and 12.1 months (95% CI: 9.6-16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0-18.4), 6.1 months (95% CI: 4.0-8.9) for CTX-based and 5.3 months (95% CI: 4.1-9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3-16.7 and CTX-based ones (95%CI: 8.7-52.8). Tumour response, PFS and OS decreased proportionally in later lines. CONCLUSION: This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.

Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial.

PURPOSE: To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC). METHODS: Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m2 + cyclophosphamide (C) 600 mg/m2 × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS). RESULTS: One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range [IQR] 24.6-50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8-10.4) in arm A and 9.9 (95% CI 7.4-11.5) in arm B (P = 0.651). In patients with HOMA index < 2.5, median PFS was 10.4 months (95% CI 9.6-11.7) versus 8.5 (95% CI 5.8-9.7) in those with HOMA index ≥ 2.5 (P = 0.034). Grade 3/4 neutropenia was the most common toxicity, occurring in 54.4% of arm A patients and 72.3% of the arm B group (P = 0.019). M induced diarrhea (G2) was observed in 8.8% of patients in Arm A. The effect of M was similar in patients with HOMA index < 2.5 and ≥ 2.5, for PFS and OS. CONCLUSIONS: The MYME trial failed to provide evidence in support of an anticancer activity of M in combination with first line CT in MBC. A significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥ 2.5). Noteworthy, M had a significant effect on CT induced severe neutropenia. Further development of M in combination with CT in the setting of MBC is not warranted.

Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer.

Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.

Detection of blood pressure increments in active elderly individuals: the role of ambulatory blood pressure monitoring.

BACKGROUND AND AIMS: Physiological aging can lead to an increase in blood pressure (BP) over time even in regularly exercising elders. Office BP measurements (OBPM) might be unable to detect these BP variations. The aim of this study was to analyze BP changes over 3.5 years in active elders using ABPM. METHODS AND RESULTS: The study involved 80 active subjects ≥65 years old who exercised regularly. At baseline and again 3.5 years later, all subjects had lab tests, weight, body mass index (BMI), body composition, resting energy expenditure (REE) recorded; they underwent OBPM, ABPM and physical activity assessment. Over 3.5 years, our sample's mean weight, BMI, body composition, REE, albumin, and physical activity levels, did not change significantly. The prevalence of hypertension detected by OBPM dropped from 68.8% to 61.3%. ABPM revealed an increase in mean 24-h BP (Δsystolic: 5.3 ± 13.6 mmHg; p = 0.001; Δdiastolic: 1.8 ± 6.7 mmHg; p = 0.018) and mean daytime BP (Δsystolic: 5.8 ± 13.5 mmHg; p = 0.001; Δdiastolic: 1.9 ± 7.1 mmHg; p = 0.022); the prevalence of hypertension detected by ABPM increased from 50% to 65%, also due to an increase (from 8.8% to 16.3%) in masked hypertension. There was no correlation between BP changes and changes in body composition and REE. CONCLUSION: BP tends to increase over time in active elders, regardless of changes in body composition or level of physical activity. ABPM is an appropriate method for detecting these BP variations in active elders and to reveal cases of masked hypertension that might otherwise escape detection by OBPM.

Final results of the real-life observational VICTOR-6 study on metronomic chemotherapy in elderly metastatic breast cancer (MBC) patients.

Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT's activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75-98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3-4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.

Changes in total body and limb composition and muscle strength after a 6-8 weeks sojourn at extreme altitude (5000-8000 m).

AIM: Weight loss at extreme altitudes affects quantitative changes in fat-free mass (FFM), muscle mass and fat mass. No studies to date have focused on regional body composition and physical performance using reference methods after stays at extreme altitudes. The aim of this study was to investigate the changes in total and regional body composition, and muscle strength induced by the extreme altitudes. METHODS: Eight men aged 38.8±5.8 who took part in two different Italian expeditions on Mt. Everest (group A) and on Gasherbrum II (group B). Before and after the expedition all participants underwent anthropometric measurements, total and regional body composition assessment by DEXA, and handgrip and knee extensor strength measurements by dynamometry. RESULTS: The variations in body composition mainly involved FFM, with a similar loss in group A (-2.4±1.9 kg; P<0.05) and group B (-2.4±1.2 kg; P<0.05). Most of the FFM loss involved the limbs (-2.1±1.4 kg; P<0.01), and especially the upper limbs (-1.6±1.1 kg; P<0.01). The isotonic knee extensor strength declined in 6 of the 8 study participants, with a mean drop of -4.4±6.1 kg. CONCLUSIONS: In conclusion, our study evidence that extreme altitudes induce weight loss due mainly to a loss of fat-free mass in the limb.

Hypovitaminosis D and fat mass in healthy older people.

Prospective studies have suggested that hypovitaminosis D can predict the onset of obesity, but they relied mainly on body mass index, which could be scarcely reliable in older people. We investigated whether baseline hypovitaminosis D could predict higher fat mass (FM) levels using dual-energy X-ray absorptiometry in a sample of 116 fit and healthy older subjects. Although no significant differences in FM estimates emerged between subjects with and without hypovitaminosis D at the baseline, abdominal FM was found significantly higher in the former group (with hypovitaminosis D at the baseline) than in the latter after 3 years of follow-up. Adjusted logistic regression analysis confirmed these findings: hypovitaminosis D coincided with an approximately sixfold higher risk of subjects having higher abdominal FM levels at the follow-up. In conclusion, hypovitaminosis D predicts higher abdominal FM levels in the elderly.

Genotoxicity of the natural cercaricides "sucupira" oil and eremanthine in mammalian cells in vitro and in vivo.

"Sucupira" oil and the lactone eremanthine, extracted from Pterodon pubescens and Eremanthus elaeagnus, respectively, are known for their cercaricidal action in experimental animals. Because of their biological effect, they have the potential to be used for the prophylaxis of schistosomiasis caused by Schistosoma mansoni. To test the clastogenicity of these agents, "sucupira" oil, either pure or diluted in corn oil, was tested in vivo on Wistar rat bone marrow cells following dermal application. Metaphase analysis showed that the compound did not induce a significant increase in the frequencies of chromosomal aberrations. When eremanthine was tested on BALB/c mice following gavage at doses of 100, 200, and 300 mg/kg bw, it did not induce structural or numerical chromosomal aberrations. In the in vitro treatment of human lymphocyte cultures, eremanthine also did not cause any increase in chromosomal aberrations or sister chromatid exchanges at the following concentrations in culture medium: 1.25, 2.50, and 5.00 micrograms/ml. From these results, under our experimental conditions, neither "sucupira" oil nor eremanthine showed clastogenic effects on mammalian cells in vivo or in vitro.

Myrcene mimics the peripheral analgesic activity of lemongrass tea.

Oral administration of an infusion of lemongrass (Cymbopogon citratus) fresh leaves to rats produced a dose-dependent analgesia for the hyperalgesia induced by subplantar injections of either carrageenin or prostaglandin E2, but did not affect that induced by dibutyryl cyclic AMP. These results indicate a peripheral site of action which was confirmed with the essential oil obtained by steam distillation of the leaves. Silica gel column fractionation of the essential oil allowed the identification of myrcene as the major analgesic component in the oil. Identification of the components was made by thin-layer chromatography and checked by mass spectrometry. The peripheral analgesic effect of myrcene was confirmed by testing a standard commercial preparation on the hyperalgesia induced by prostaglandin in the rat paw test and upon the contortions induced by intraperitoneal injections of iloprost in mice. In contrast to the central analgesic effect of morphine, myrcene did not cause tolerance on repeated injection in rats. This analgesic activity supports the use of lemongrass tea as a "sedative" in folk medicine. Terpenes such as myrcene may constitute a lead for the development of new peripheral analgesics with a profile of action different from that of the aspirin-like drugs.

Anti-inflammatory activity of cubebin, a lignan from the leaves of Zanthoxyllum naranjillo Griseb.

Cubebin, a dibenzylbutyrolactone lignan isolated from the crude hexane extract of the leaves of Zanthoxyllum naranjillo, showed a significant anti-inflammatory activity by using the paw edema induced by carrageenin in rats, but did not provide a significant reduction in the cell migration for the acute carrageenin-induced inflammatory reaction in the peritoneal cavity of rats. Neither was it effective in reducing the edema induced by dextran nor the edema induced by histamine. It partially reduced the edema induced by serotonin. Moreover, it significantly reduced the edema induced by prostaglandin PGE2 and the number of writhings induced by both acetic acid and PGI2 in mice. Therefore, it may be suggested that the mechanism of action of cubebin is similar to that observed for most of the non-steroidal drugs.

Preliminary studies of analgesic and anti-inflammatory properties of Caesalpinia ferrea crude extract.

The crude aqueous extract of the fruits of Caesalpinia ferrea Mart. (Leguminosae) has been investigated for possible anti-inflammatory and analgesic properties. The carrageenan induced rat hind paw edema was significantly inhibited (P < 0.05) by oral administration of 300 mg/kg of this extract. A centrally mediated analgesic effect was not observed, however, there was a dose dependent reduction in the number of total writhes induced by acetic acid.

Anti-inflammatory activity of the crude extract from the fruits of Pterodon emarginatus Vog.

The vegetal species Pterodon emarginatus Vog. (Leguminosae/Papilonaceae), popularly known in Brazil as 'sucupira branca', is widely used by domestic medicine as an anti-inflammatory. From these observations, the hexanic crude extract (HCE) of the fruits was obtained and submitted for assessment of its anti-inflammatory activity. For this purpose, the following tests were used: (1) Determination of ED50 and LD50; (2) Paw edema induced by carrageenin, dextran, histamine and nystatin; (3) Peritonitis caused by carrageenin and (4) Granuloma test. The ED50 (oral) in the edema induced by carrageenin was 500 mg/kg, and LD50 (oral) was 4.02 g/kg. In the edema caused by nystatin, there was a significant inhibition by 45% (P < 0.05 student's t-test) at the 6th hour following the treatment. In the granuloma test performed in animals treated with HCE, there was an inhibition of the granulomatous tissue formation by 22%. The migration of neutrophils towards the peritoneal cavity was inhibited in HCE treated animals by 43% (P < 0.05). However, in the edema caused by dextran and histamine, there was no significant response in HCE treated animals.

Anti-inflammatory activity of flavone and some of its derivates from Virola michelli Heckel.

The phytochemical study using Virola michelli Heckel (Myristicaceae) leaves allowed the isolation of a flavone named titonine (7,4'-dimethoxy-3'-hydroxyflavone). Titonine was further submitted to methylation and acetylation reactions yielding a 7,3',4'-trimethoxyflavone and a 7,3'-dimethoxy-4'-acetylflavone, respectively. These compounds were evaluated for both anti-inflammatory and analgesic activity. The anti-inflammatory activity was evaluated in rats using the paw edema test with carrageenin, while the analgesic activity was determined in mouse using the writhing test method. The different animal groups were treated with three compounds (10 mg/kg -i.p.) thirty min prior to stimuli application. The inhibition levels obtained for each compound were 22, 41 and 68%, respectively. Using the writhing test, oral doses of 5, 10 and 15 mg/kg of natural flavone reduced the acetic acid-induced contortions in a dose-dependent manner.

[Chemoprophylactic activity on Schistosomiasis mansoni of soaps containing essential oil from the fruits of Pterodon pubescens]. / Atividade quimioprofilática na esquistossomose mansoni de sabonetes contendo óleo essencial de frutos de Pterodon pubescens.

The chemoprophylactic action of the essential oil of the fruit of Pterodon pubescens Benth (Leguminosae), incorporated in different soap formulations, was studied in experimental schistosomiasis. The formulations were used locally on the tails of mice which were exposed to Schistosoma mansoni cercariae immediately, 24, 72 or 168 hours later by the method of tail immersion. Protection was evaluated 45 days after exposure when the mice were sacrificed and the worms collected by perfusion. The results showed levels of protection varying from 0.0 to 100% depending on the formulation used. A methodology that allowed the evaluation of soap protection of mice exposed to natural infection in snail infested streams on the outskirts of Belo Horizonte, MG, was also developed. Promising results were obtained in that protection of between 57.5 and 31.1% was observed in field trials when soap was applied to the animals 24 and 48 hours earlier. Preliminary studies evaluating irritation and toxicity were favorable and showed that this new prophylactic weapon could contribute to the control of schistosomiasis.

Efficacy of specific bioelectrical impedance vector analysis (BIVA) for assessing body composition in the elderly.

OBJECTIVES: This study aimed to ascertain the efficacy of bioelectrical impedance vector analysis (BIVA) in assessing body composition in the elderly by comparing findings with the results of dual-energy X-ray absorptiometry (DXA), and to test an analytical variant of the method (specific BIVA). DESIGN: Cross-sectional study. PARTICIPANTS: The sample comprised 207 free-living elderly individuals (75 men and 132 women) aged 65 to 93 years. MEASUREMENTS: Anthropometric and bioelectrical measurements were taken according to standard criteria. BIVA was applied using the 'classic' procedure and correcting bioelectrical values for body geometry to obtain an estimate of the whole-body impedivity. DXA was used as a reference body composition assessment method. BIVA (classic and specific values) and DXA findings were compared using Student's t and Hotelling's T2 tests, and Pearson's correlation coefficient. RESULTS: In both sexes, BIVA distinguished between individuals with different amounts of fat and fat-free mass (lean mass including bone mineral content), according to DXA, but not between those with different proportions of fat mass (FM%). Specific bioelectrical values detected changes in body composition. CONCLUSION: BIVA should be used with caution for evaluating body composition in the elderly. Specific bioelectrical values proved effective, showing promise as a methodological variant of BIVA, suitable for identifying age-related changes in body fatness.

Hydrogen bond network relaxation in aqueous polyelectrolyte solutions: the effect of temperature.

Dielectric spectroscopy data over the range 100 MHz­40 GHz allow for a reliable analysis of two of the major relaxation phenomena for polyelectrolytes (PE) in water. Within this range, the dielectric relaxation of pure water is dominated by a near-Debye process at ν = 18.5 GHz corresponding to a relaxation time of τ = 8.4 ps at 25 °C. This mode is commonly attributed to the cooperative relaxation specific to liquids forming a hydrogen bond network (HBN) and arising from long range H-bond-mediated dipole­dipole interactions. The presence of charged polymers in water partially modifies the dielectric characteristics of the orientational water molecule relaxation due to a change of the dielectric constant of water surrounding the charges on the polyion chain. We report experimental results on the effect of the presence of a standard flexible polyelectrolyte (sodium polyacrylate) on the HBN relaxation in water for different temperatures, showing that the HBN relaxation time does not change by increasing the polyelectrolyte density in water, even if relatively high concentrations are reached (0.02 monomol l(−1) ≤ C ≤ 0.4 monomol l(−1)). We also find that the effect of PE addition on the HBN relaxation is not even a broadening of its distribution, rather a decrease of the spectral weight that goes beyond the pure volume fraction effect. This extra decrease is larger at low T and less evident at high T, supporting the idea that the correlation length of the water is less affected by the presence of charged flexible chains at high temperatures.